The overall goal of this program project is cooperative research among the laboratories studying oncogenic retroviruses and oncogenes at the Fred Hutchinson Cancer Research Center. This renewal proposes continued analysis in experimental systems of viral and cellular genes involved in neoplasia. This analysis will be directed at two groups of oncogenes: one group which mediates mitogenic signal transduction from the cell surface and the second which acts in the cell nucleus to regulate patterns of gene expression and cellular growth. The program consists of six projects. Projects l and 6 are concerned with oncogenic growth factor receptor proteins including the platelet derived growth factor (PDGF) receptor, the M-CSF receptor fms and the c-kit receptor. Studies will analyze pathways of signal transduction through these receptors and genes which can regulate these pathways. Projects 2-5 are concerned with nuclear acting oncogenes including myc and erbA. Experiments are directed at analyzing the roles of these genes both in early development in Xenopus and in B-cell development in the immune system. In addition, molecular mechanism of action of the myc protein will be explored by analysis of proteins with which it associates and genes whose expression is regulated by myc including the negative autoregulation of c-myc expression. The mechanism of transcriptional regulation of c-myc by control of initiation and blocks to elongation will be explored including the mechanism of deregulation of myc by rearrangement and mutation of the myc locus. A series of novel v-myc transducting viruses with altered transforming potential will be analyzed and the role of viral gag plO protein in infectivity will be determined. The project will be supported by a core component which provides shared animal research facilities and media production. Interactions between cooperative laboratory groups will be enhanced by a weekly research meeting and by an annual scientific meeting with investigators from other institutions with shared interests.